DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status and Withdrawn Rejections
Applicant’s amendment filed August 27, 2026, amending claims 1 and 4, is acknowledged. Claims 1-4 are pending and under examination.
The amendment to claim 1 requiring the ETV3 and ETV6 inhibitors to be RNA oligonucleotides and removing the option for a ribozyme in claim 4 overcomes the §112(a) rejection.
Any other rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Marzaioli (Marzaioli et al., Blood (2017), 130: 1734-1745; of record), in view of Lau (Lau et al., Journal of Experimental Medicine (2018), 215: 2265-2278; of record), Goudot (Goudot et al., Immunity (2017), 47: 582-596), Fisher (Fisher et al., JCI insight (2020), 5(18), e140332; of record) and Hu (Hu et al., Signal Transduction and Targeted Therapy (2020), 5:101, pages 1-25; of record). This is a maintained rejection.
Regarding claims 1-2 and 4, Marzaioli teaches inflammatory dendritic cells (DCs) are derived from monocytes and can be referred to as monocyte-derived dendritic cells (Mo-DCs) (page 1734, ¶1). Marzaioli teaches during infection, circulating monocytes emigrate from bone marrow into circulation where they differentiate into DCs, which then maturate and acquire T-cell stimulatory functions (page 1734, ¶1). Marzaioli teaches limiting differentiation of monocytes into Mo-DCs could be a beneficial strategy to treat human inflammatory diseases (¶ spanning pages 1734-1735). Marzaioli teaches the activity of NOX5 promotes Mo-DC differentiation (Fig 7). Marzaioli teaches administering siRNAs (i.e., an inhibitor that is an RNA oligonucleotide) targeting NOX5 reduces Mo-DC differentiation (Fig 4E, page 1741, ¶1).
Marzaioli does not teach providing an siRNA targeted to ETV6 or ETV3 for the purpose of inhibiting Mo-DC differentiation.
Lau teaches the ETV6 transcription factor regulates differentiation of dendritic cells (Title). Lau teaches that ETV6 is expressed primarily in DCs and monocytes (page 2266, ¶3). Lau teaches knocking out ETV6 specifically in bone marrow cells impaired differentiation of DC cells (page 2266, ¶5).
Goudot teaches that ETV6 is highly expressed in Mo-DCs, but not in monocyte-derived macrophages (Fig 2).
Fisher teaches treating peripheral blood mononuclear cells (PBMCs) (i.e., including monocytes) with an siRNA targeting ETV6 (page 3, ¶2; page 11, ¶1).
Hu teaches the state of the art of siRNA therapies as of 2020 (Title). Hu teaches several siRNA therapies have FDA and EC approval (page 1, ¶3). Hu teaches that siRNAs can be formulated for targeted in vivo delivery (throughout).
Regarding claims 1, 2 and 4, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Fisher’s siRNA in Marzaioli’s method of inhibiting Mo-DC differentiation specifically in a subject suffering from an inflammatory disease. It would have amounted to the simple combination of elements by known means to yield predictable results. Starting from Marzaioli and looking for alternative approaches to block the differentiation of monocytes into dendritic cells, the skilled person would have been motivated to use an ETV6 siRNA, since Lau teaches ETV6 was known to be required for the differentiation of dendritic cells and Goudot teaches upregulation of ETV6 during monocyte-to-DC differentiation but not monocyte-to-macrophage differentiation. The skilled artisan would have predicted that an ETV6 siRNA could be delivered to a patient because Fisher teaches delivering siRNA to bone-marrow derived cells and Hu teaches that siRNA-delivery is well known in the art.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Marzaioli (Marzaioli et al., Blood (2017), 130: 1734-1745; of record), Lau (Lau et al., Journal of Experimental Medicine (2018), 215: 2265-2278; of record), Goudot (Goudot et al., Immunity (2017), 47: 582-596; of record), Fisher (Fisher et al., JCI insight (2020), 5(18), e140332; of record) and Hu (Hu et al., Signal Transduction and Targeted Therapy (2020), 5:101, pages 1-25; of record), as applied to claims 1-2 and 4 above, and further in view of Wu (Wu and Laufer, Current Neurology and Neuroscience Reports (2007), 7: 245-252; of record).
The teachings of Marzaioli, Lua, Goudot, Fisher and Hu are recited above and applied as for claims 1-2 and 4. Hu also teaches central nervous system (CNS)-targeted siRNA delivery platforms have been established (page 20, ¶3).
Marzaioli, Lua, Goudot, Fisher and Hu do not teach the role of dendritic cells in multiple sclerosis (MS).
Wu teaches the clinical and pathological features of MS point to an immune-mediated pathogenesis (page 245, ¶1). Wu teaches that DCs are ultimately culpable for the generation of autoreactive T-cell activity in MS (page 245, ¶1). Wu teaches there is an increased abundance of DCs in the CNS of MS patients (page 248, ¶2). Wu teaches in MS patients, monocyte-derived DCs secrete IL-23, which in turn support Th-17 polarization of T cells (page 248, ¶4).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the ETV6-targeted siRNA treatment method rendered obvious above specifically to prevent DC differentiation from monocytes in MS patients. It would have amounted to modifying a known siRNA for delivery to circulation and CNS by known means for treatment of a disease that is known to have a monocyte-derived DC pathological component. The skilled artisan would have been motivated to specifically treat MS patients since it was well established that DCs play a role in MS pathology. It was entirely predictable that siRNAs targeting ETV6 could be administered to MS patients for the purpose of reduced monocyte-derived DC differentiation because Hu teaches siRNA delivery means to both systemic circulation and the CNS have been developed.
Response to Arguments
Applicant argues that the NOX5 gene used to prevent Mo-to-DC differentiation in Marzaioli has a different function and cellular localization than ETV3 and ETV6 and that the skilled artisan would not have been motivated to inhibit a protein with a different cellular function to prevent Mo-DC differentiation. Applicant argues Marzaioli thus teaches away from the invention (Remarks, ¶ spanning pages 4-5). This argument has been fully considered but is not persuasive. First, as the rejection of record recites, the skilled artisan looking for different means for inhibiting Mo-DC differentiation would consider ETV6 siRNA because it was previously known to promote DC differentiation and highly expressed in mo-DCs as evidenced by Lau and Goudot. It is well known in the art that cellular/signaling pathways involve different proteins in different cellular localizations, including membrane and nuclear proteins, to transmit an extracellular signal and culminate in a cellular response, which is often a change in gene expression. For instance, Figure 7 of Marzaioli illustrates such a pathway initiating from a cell membrane receptor and ending in a change in gene expression. Thus, a difference in protein function and/or localization in the cell would not dissuade the skilled artisan from inhibiting a different protein known to be involved in mo-DC differentiation. Second, Examiner disagrees that Marzaioli “teaches away” from the claimed invention. Marzaioli is completely silent on inhibiting ETV3 or ETV6 or even inhibiting transcription factors. Because Marzaioli is silent as to ETV3, ETV6 and inhibiting transcription factors, they cannot also “teach away” from it.
Applicant argues that the data in Lau would not suggest to the skilled artisan that inhibiting ETV3 or ETV6 in monocytes would redirect differentiation to mo-MAC phenotypes (page 4, ¶2). This argument has been fully considered but is not persuasive because it is directed to limitations that are not recited in the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims merely recite “a method for blocking differentiation of monocytes into dendritic cells”. The claims do not require the monocytes to be differentiated in macrophages or mo-MACs. Additionally, the claims are generic as to the type of dendritic cell for which differentiation is blocked.
Applicant argues that Goudot also teaches away from the importance of ETV3 and/or ETV6 in Mo-DC differentiation (¶ spanning pages 5-6). This argument has been fully considered but is not persuasive because no where in Goudot do the authors recite “do not use ETV3 or ETV6 to block differentiation” or “ETV3 and ETV6 are not significant to the differentiation of dendritic cells”. Goudot is used as another piece of prior art evidence to support the notion that ETV6 was previously understood to promote mo-DC differentiation.
Applicant argues that Fisher and Hu do not teach the role of ETV3 and/or ETV6 in monocyte differentiation therefore do not cure the deficiencies of Marzaioli, Lau and Goudot (page 5, ¶2). This argument has been fully considered but is not persuasive since Fisher and Hu were not relied upon for teaching the role of ETV3 and ETV6, which was established with Lau and Goudot. Therefore, Applicant’s arguments do not address the merits of the rejection.
Applicant argues that Wu [sic] does not cure the deficiencies of Marzaioli, Lau, Goudot, Fisher and Hu (page 5, ¶3 through page 6, ¶2). This argument has been fully considered but is not persuasive because a prima facie case of obviousness is established for claim 1 for the reasons set for in the §103 rejections of record and the response to Applicant’s arguments above.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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